Our long-term goal is to elucidate how environmental factors lead to autoimmune diabetes. We are particularly interested in understanding the interplay between environmental factors such as viruses and bacteria and regulatory CD4+CD25 + T cells and how these interactions lead to diabetes induction. Viral infections are thought to play a key role in the development of autoimmune diabetes in genetically susceptible individuals. Although data obtained from humans support this assumption, little is known regarding the underlying mechanisms. It is exceedingly difficult to conduct human studies of the interaction between the environment and genetic predisposition, and the NOD mouse models this process poorly because the overwhelming majority of perturbants reduce the frequency of diabetes and often prevent it entirely. The diabetes-resistant BB (BBDR) rat exhibits a normal phenotype of their immune system. Spontaneous diabetes does not occur in viral antibody free BBDR rats, but autoimmunity can be induced following an exposure to environmental perturbants such as the parvovirus Kilham's rat virus (KRV), various purified toll-like receptor(TLR) ligands, inactivated bacteria, and elimination of regulatory T cells. Hence, the BBDR rat provides a unique and powerful animal model for the analysis of mechanisms underlying environmentally induced autoimmune diabetes. Recent data from animal models demonstrate that CD4+CD25 + T cells play a major role in regulating autoimmune diabetes. We have previously reported that infection with KRV modulatesCD4+CD25 + regulatory T cells in BBDR rats and hypothesized that this is one of the mechanisms that lead to autoimmune diabetes. We will use the BBDR rat to address three Specific Aims. Specific Aim 1 is to identify how KRV infection and TLR ligation alter regulatory CD4+CD25 + T cells. We will test the hypothesis that infection with KRV leads to an altered ability of Treg cells to regulate autoreacive T cells. Specific Aim 2 is to determine the role of DCs in regulating CD4+CD25 + T cell function. We will test the hypothesis that CD4+CD25 + T cell modulation following KRV infection is mediated via activated DCs. Specific Aim 3 is to prevent virus-induced diabetes by inducing up-regulation of CD4+CD25 + suppressor T cells or by altering DC function. We will determine whether KRV-induced autoimmunity can be blocked by treating BBDR rats with agents that induce up-regulation of CD4+CD25 + T cells or down-modulate functions of DCs. It is our belief that new information obtained in these studies will greatly advance our understanding of mechanisms by which environmental factors lead to autoimmune diabetes. This may lead to the development of new clinical approaches to combat diabetes in humans.